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http://dx.doi.org/10.2147/COPD.S100352
Combining systems pharmacology, transcriptomics, proteomics, and metabolomics to dissect the therapeutic mechanism of Chinese herbal Bufei Jianpi formula for application to COPD
Peng Zhao1,2
liping Yang1,2
Jiansheng li1,2
Ya li1,2
Yange Tian1,2
suyun li2,3
1Key laboratory of Chinese Internal Medicine, henan University of Traditional Chinese Medicine, 2Collaborative Innovation Center for respiratory Disease Diagnosis and Treatment and Chinese Medicine Development of henan Province, 3Department of respiratory Diseases, The First affiliated hospital of henan University of Traditional Chinese Medicine, Zhengzhou, People’s republic of China
Abstract: Bufei Jianpi formula (BJF) has long been used as a therapeutic agent in the treatment
of COPD. Systems pharmacology identified 145 active compounds and 175 potential targets of
BJF in a previous study. Additionally, BJF was previously shown to effectively prevent COPD
and its comorbidities, such as ventricular hypertrophy, by inhibition of inflammatory cytokine
production, matrix metalloproteinases expression, and other cytokine production, in vivo.
However, the system-level mechanism of BJF for the treatment of COPD is still unclear. The aim
of this study was to gain insight into its system-level mechanisms by integrating transcriptomics,
proteomics, and metabolomics together with systems pharmacology datasets. Using molecular
function, pathway, and network analyses, the genes and proteins regulated in COPD rats and
BJF-treated rats could be mainly attributed to oxidoreductase activity, antioxidant activity, focal
adhesion, tight junction, or adherens junction. Furthermore, a comprehensive analysis of systems
pharmacology, transcript, protein, and metabolite datasets is performed. The results showed that
a number of genes, proteins, metabolites regulated in BJF-treated rats and potential target pro-
teins of BJF were involved in lipid metabolism, cell junction, oxidative stress, and inflammatory
response, which might be the system-level therapeutic mechanism of BJF treatment.
IntroductionCOPD is a serious health problem characterized primarily by irreversible airflow limi-
tation and systemic inflammation, which represents a substantial economic burden in
the world.1,2 Despite great progress in the treatment of COPD, drug therapies have not
changed significantly.3 Therefore, the development of novel therapeutic drugs and strate-
gies to improve the efficacy in treating this deadly disease is still urgently needed.
Bufei Jianpi formula (BJF), a traditional Chinese medicine (TCM), has provided
effective relief of symptoms in patients with COPD. Our clinical study demonstrated
that BJF had extensive pharmacological effects on patients with COPD, such as alleviat-
ing the clinical symptoms of stable COPD, reducing the exacerbation frequency, delay-
ing acute exacerbation, and improving pulmonary function and exercise capacity.4
Increasing evidences demonstrate that, in treating complex illnesses, includ-
ing COPD, treatment formula containing multiple drugs with distinct but related
mechanisms can usually exert synergistic therapeutic effects and amplify the
Correspondence: Jiansheng lihenan University of Traditional Chinese Medicine, 1 Jinshui road, Zhengzhou 450046, People’s republic of ChinaTel +86 371 6567 6568email [email protected]
Journal name: International Journal of COPDArticle Designation: Original ResearchYear: 2016Volume: 11Running head verso: Zhao et alRunning head recto: Chinese herbal Bufei Jianpi formula for COPDDOI: http://dx.doi.org/10.2147/COPD.S100352
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Chinese herbal Bufei Jianpi formula for COPD
Figure 3 Pathway analysis of the metabolites regulated in lung tissues of COPD rats and BJF-treated rats.Notes: global metabolic disorders of the most relevant pathways were revealed using the Metaboanalyst. a google-map style interactive visualization system was implemented to facilitate data exploration and generate pathway views. (A) representative pathway analysis of the metabolites in lung tissues of COPD rats. (B) representative pathway analysis of the metabolites in lung tissues of BJF-treated rats.Abbreviation: BJF, Bufei Jianpi formula.
Figure 4 Correlation networks of the metabolites, genes, and proteins regulated in lung tissues of COPD rats and BJF-treated rats.Notes: The compound reaction network with compounds (the pink and red hexagons) and metabolic enzymes (the gray and blue rounds) as nodes and reactions as edges, was constructed using Metscape. Inputted compounds are shown in red, inputted genes and proteins are shown in blue. existing compounds that populate the Metscape system were shown in pink. existing genes and proteins were shown in gray. (A) representative metabolites–gene network of COPD model group. (B) representative metabolite–gene network of the BJF-treated group. (C) representative metabolites–protein network of the COPD model group. (D) representative metabolite–protein network of the BJF-treated group.Abbreviation: BJF, Bufei Jianpi formula.
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Chinese herbal Bufei Jianpi formula for COPD
Figure 6 Correlation networks of the metabolites regulated in BJF-treated rats and target proteins.Notes: The compound reaction network with compounds (the pink and red hexagons) and metabolic enzymes (the gray and blue rounds) as nodes and reactions as edges, was constructed using Metscape. Inputted compounds are shown in red, and inputted target proteins are shown in blue. existing compounds that populate the Metscape system were shown in pink. existing proteins were shown in gray.Abbreviation: BJF, Bufei Jianpi formula.
Figure 7 Comprehensive analysis of the potential targets of BJF, transcriptomics, proteomics, and metabolomics regulations in lung tissues of BJF-treated rats.Notes: The potential targets, transcriptomics, proteomics, and metabolomics data are presented as rectangles with different colors. red arrow stands for upregulated, blue arrow for downregulated, and gray rectangle for unregulated.Abbreviation: BJF, Bufei Jianpi formula.
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Chinese herbal Bufei Jianpi formula for COPD
AcknowledgmentsThe research is supported by the National Natural Science
Fund of China (influence and long-term effects of three
Tiao-Bu Fei-Shen therapies in rats with COPD on regulation
of multidimensional molecular network, No 81130062).
Authors contributionsJSL and SYL designed the outline of the study. PZ performed
experiments, conceived the study, wrote the draft of the
manuscript, and revised the manuscript. LPY, YGT, and YL
were involved in performing experiments, acquisition of data,
and statistical analysis. All authors contributed toward data
analysis, drafting and critically revising the paper and agree
to be accountable for all aspects of the work. All the authors
read and approved the final version of the manuscript.
DisclosureThe authors report no conflicts of interest in this study.
References 1. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis,
management, and prevention of chronic obstructive pulmonary disease GOLD executive summary. Am J Respir Crit Care Med. 2013;187: 347–365.
2. Bafadhel M, McCormick M, Saha S, et al. Profiling of sputum inflam-matory mediators in asthma and chronic obstructive pulmonary disease. Respiration. 2012;83:36–44.
3. Woodruff PG, Agusti A, Roche N, Singh D, Martinez FJ. Current concepts in targeting chronic obstructive pulmonary disease pharma-cotherapy: making progress towards personalised management. Lancet. 2015;385:1789–1798.
4. Li SY, Li JS, Wang MH, et al. Effects of comprehensive therapy based on traditional Chinese medicine patterns in stable chronic obstructive pulmonary disease: a four-center, open-label, randomized, controlled study. BMC Complement Altern Med. 2012;12:197.
5. Li S. Network systems underlying traditional Chinese medicine syn-drome and herb formula. Curr Bioinform. 2009;4:188–196.
6. Jia W, Gao WY, Yan YQ, et al. The rediscovery of ancient Chinese herbal formulas. Phytother Res. 2004;18:681–686.
7. Zhao P, Li J, Li Y, Tian Y, Wang Y, Zheng C. Systems pharmacology-based approach for dissecting the active ingredients and potential targets of the Chinese herbal Bufei Jianpi formula for the treatment of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:2633–2656.
8. Huang Q, Tan YX, Yin PY, et al. Metabolic characterization of hepa-tocellular carcinoma using nontargeted tissue metabolomics. Cancer Res. 2013;73:4992–5002.
9. Heijne WH, Kienhuis AS, van Ommen B, Stierum RH, Groten JP. Systems toxicology: applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology. Expert Rev Proteomics. 2005;2: 767–780.
10. Meierhofer D, Weidner C, Sauer S. Integrative analysis of transcriptomics, proteomics, and metabolomics data of white adipose and liver tissue of high-fat diet and rosiglitazone-treated insulin-resistant mice identified pathway alterations and molecular hubs. J Proteome Res. 2014;13:5592–5602.
11. Su G, Burant CF, Beecher CW, Athey BD, Meng F. Integrated metabolome and transcriptome analysis of the NCI60 dataset. BMC Bioinformatics. 2011;12(suppl 1):S36.
12. Gehlenborg N, O’Donoghue SI, Baliga NS, et al. Visualization of omics data for systems biology. Nat Methods. 2010;7:S56–S68.
13. Li JS, Yang LP, Li Y, et al. Metabolomics study on model rats of chronic obstructive pulmonary disease treated with Bu-Fei Jian-Pi. Mol Med Rep. 2015;11:1324–1333.
14. Li Y, Li SY, Li JS, et al. A rat model for stable chronic obstructive pulmonary disease induced by cigarette smoke inhalation and repetitive bacterial infection. Biol Pharm Bull. 2012;35:1752–1760.
15. Maere S, Heymans K, Kuiper M. BiNGO: a cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 2005;21:3448–3449.
16. Karnovsky A, Weymouth T, Hull T, et al. Metscape 2 bioinformatics tool for the analysis and visualization of metabolomics and gene expres-sion data. Bioinformatics. 2012;28:373–380.
17. Bindea G, Mlecnik B, Hackl H, et al. ClueGO: a cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25:1091–1093.
18. Xia JG, Sinelnikov IV, Han B, Wishart DS. MetaboAnalyst 3.0-making metabolomics more meaningful. Nucleic Acids Res. 2015;43: W251–W257.
19. Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–D452.
20. MacNee W. Pathogenesis of chronic obstructive pulmonary disease. Clin Chest Med. 2007;28:479–513.
21. Barnes PJ, Stockley RA. COPD: current therapeutic interventions and future approaches. Eur Respir J. 2005;25:1084–1106.
22. Tufvesson E, Bjermer L, Ekberg M. Patients with chronic obstructive pulmonary disease and chronically colonized with Haemophilus influ-enzae during stable disease phase have increased airway inflammation. Int J Chron Obstruct Pulmon Dis. 2015;10:881–889.
23. Tulah AS, Parker SG, Moffatt MF, Wardlaw AJ, Connolly MJ, Sayers I. The role of ALOX5AP, LTA4H and LTB4R polymorphisms in deter-mining baseline lung function and COPD susceptibility in UK smokers. BMC Med Genet. 2011;12:173.
24. Wang R, Li M, Zhou S, et al. Effect of a single nucleotide polymorphism in miR-146a on COX-2 protein expression and lung function in smok-ers with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:463–473.
25. Hoffmeyer F, Harth V, Bunger J, Bruning T, Raulf-Heimsoth M. Leukotriene B4, 8-iso-prostaglandin F2 alpha, and pH in exhaled breath condensate from asymptomatic smokers. J Physiol Pharmacol. 2009; 60(suppl 5):57–60.
26. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. 2006;28:219–242.
27. Rahman I, MacNee W. Antioxidant pharmacological therapies for COPD. Curr Opin Pharmacol. 2012;12:256–265.
28. Inonu H, Doruk S, Sahin S, et al. Oxidative stress levels in exhaled breath condensate associated with COPD and smoking. Respir Care. 2012;57:413–419.
29. Harju T, Kaarteenaho-Wiik R, Sirvio R, et al. Manganese superoxide dismutase is increased in the airways of smokers’ lungs. Eur Respir J. 2004;24:765–771.
30. Tanaka K, Sato K, Aoshiba K, Azuma A, Mizushima T. Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice. Am J Physiol Lung Cell Mol Physiol. 2012;302:L1250–L1261.
31. Lakhdar R, Denden S, Mouhamed MH, et al. Correlation of EPHX1, GSTP1, GSTM1, and GSTT1 genetic polymorphisms with antioxidative stress markers in chronic obstructive pulmonary disease. Exp Lung Res. 2011;37:195–204.
32. Park HY, Man SF, Tashkin D, et al. The relation of serum myeloper-oxidase to disease progression and mortality in patients with chronic obstructive pulmonary disease (COPD). PLoS One. 2013;8: e61315.
33. Churg A, Marshall CV, Sin DD, et al. Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185: 34–43.
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International Journal of COPD 2016:11submit your manuscript | www.dovepress.com
Dovepress
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Zhao et al
34. Hsu AC, Starkey MR, Hanish I, et al. Targeting PI3K-p110alpha suppresses influenza virus infection in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:1012–1023.
35. Huang Y, Meng XM, Jiang GL, et al. Studies on mitogen-activated protein kinase signaling pathway in the alveolar macrophages of chronic bronchitis rats. Mol Cell Biochem. 2015;400:97–105.
36. Mitani A, Ito K, Vuppusetty C, Barnes PJ, Mercado N. Restoration of cor-ticosteroid sensitivity in chronic obstructive pulmonary disease by inhibi-tion of mammalian target of rapamycin. Am J Respir Crit Care Med. 2016; 193:143–153.
37. Quintana-Murci L, Chaix R, Wells RS, et al. Where west meets east: the complex mtDNA landscape of the southwest and Central Asian corridor. Am J Hum Genet. 2004;74:827–845.
38. Zhang A, Sun H, Wang Z, Sun W, Wang P, Wang X. Metabolomics: towards understanding traditional Chinese medicine. Planta Med. 2010;76:2026–2035.